Human Wharton's Jelly-Derived Stem Cells Display Immunomodulatory Properties and Transiently Improve Rat Experimental Autoimmune Encephalomyelitis

• Published in: Cell transplantation Vol. 24; no. 10; pp. 2077 - 2098
• Main Authors: Donders, Raf, Vanheusden, Marjan, Bogie, Jeroen F. J., Ravanidis, Stylianos, Thewissen, Kristof, Stinissen, Piet, Gyselaers, Wilfried, Hendriks, Jerome J. A., Hellings, Niels
• Format: Journal Article
• Language: English
• Published: Los Angeles, CA SAGE Publications 01.10.2015; SAGE Publishing
• Subjects: Animals; Cell Differentiation - immunology; Cell Differentiation - physiology; Cell Proliferation - physiology; Cytokines - metabolism; Encephalomyelitis, Autoimmune, Experimental - therapy; Humans; Lymphocyte Activation - immunology; Mesenchymal Stromal Cells - cytology; Rats; T-Lymphocytes - cytology; T-Lymphocytes - immunology; Umbilical Cord - cytology; Wharton Jelly - cytology; Transplantation; Mesenchymal stem cells (MSCs); Cell therapy; Wharton's jelly; Multiple sclerosis (MS); Immunomodulation
• ISSN: 0963-6897; 1555-3892; 1555-3892
• DOI: 10.3727/096368914X685104

Umbilical cord matrix or Wharton's jelly-derived stromal cells (WJ-MSCs) are an easily accessible source of mesenchymal-like stem cells. Recent studies describe a hypoimmunogenic phenotype, multipotent differentiation potential, and trophic support function for WJ-MSCs, with variable clinical benefit in degenerative disease models such as stroke, myocardial infarction, and Parkinson's disease. It remains unclear whether WJ-MSCs have therapeutic value for multiple sclerosis (MS), where autoimmune-mediated demyelination and neurodegeneration need to be halted. In this study, we investigated whether WJ-MSCs possess the required properties to effectively and durably reverse these pathological hallmarks and whether they survive in an inflammatory environment after transplantation. WJ-MSCs displayed a lowly immunogenic phenotype and showed intrinsic expression of neurotrophic factors and a variety of anti-inflammatory molecules. Furthermore, they dose-dependently suppressed proliferation of activated T cells using contact-dependent and paracrine mechanisms. Indoleamine 2,3-dioxygenase 1 was identified as one of the main effector molecules responsible for the observed T-cell suppression. The immune-modulatory phenotype of WJ-MSCs was further enhanced after proinflammatory cytokine treatment in vitro (licensing). In addition to their effect on adaptive immunity, WJ-MSCs interfered with dendritic cell differentiation and maturation, thus directly affecting antigen presentation and therefore T-cell priming. Systemically infused WJ-MSCs potently but transiently ameliorated experimental autoimmune encephalomyelitis (EAE), an animal model for MS, when injected at onset or during chronic disease. This protective effect was paralleled with a reduction in autoantigen-induced T-cell proliferation, confirming their immunomodulatory activity in vivo. Surprisingly, in vitro licensed WJ-MSCs did not ameliorate EAE, indicative of a fast rejection as a result of enhanced immunogenicity. Collectively, we show that WJ-MSCs have trophic support properties and effectively modulate immune cell functioning both in vitro and in the EAE model, suggesting WJ-MSC may hold promise for MS therapy. Future research is needed to optimize survival of stem cells and enhance clinical durability.